scholarly journals Pharmacodynamics of antibiotics with respect to bacterial killing of and release of lipoteichoic acid by Streptococcus pneumoniae

2005 ◽  
Vol 56 (1) ◽  
pp. 154-159 ◽  
Author(s):  
Herman Mattie ◽  
Kristin Stuertz ◽  
Roland Nau ◽  
Jaap T. van Dissel
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lipoteichoic Acid ◽  
Bacterial Killing

scholarly journals Pharmacodynamics of Moxifloxacin and Levofloxacin at Simulated Epithelial Lining Fluid Drug Concentrations against Streptococcus pneumoniae

2004 ◽  
Vol 48 (4) ◽  
pp. 1215-1221 ◽  
Author(s):  
Naomi R. Florea ◽  
Pamela R. Tessier ◽  
Cuilian Zhang ◽  
Charles H. Nightingale ◽  
David P. Nicolau
Keyword(s):  
Streptococcus Pneumoniae ◽  
Fluoroquinolone Resistance ◽  
Epithelial Lining ◽  
Time Curve ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Log Reduction ◽  
Development Of Resistance ◽  
Drug Concentrations

ABSTRACT Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC, gyrA, and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.

scholarly journals Streptococcus pneumoniae DNA Gyrase and Topoisomerase IV: Overexpression, Purification, and Differential Inhibition by Fluoroquinolones

1999 ◽  
Vol 43 (5) ◽  
pp. 1129-1136 ◽  
Author(s):  
Xiao-Su Pan ◽  
L. Mark Fisher
Keyword(s):  
Streptococcus Pneumoniae ◽  
Dna Gyrase ◽  
Dna Supercoiling ◽  
Topoisomerase Iv ◽  
T7 Promoter ◽  
Bacterial Killing ◽  
E Coli ◽  
Apparent Homogeneity ◽  
Comparable Activity

ABSTRACT Streptococcus pneumoniae gyrA and gyrBgenes specifying the DNA gyrase subunits have been cloned into pET plasmid vectors under the control of an inducible T7 promoter and have been separately expressed in Escherichia coli. Soluble 97-kDa GyrA and 72-kDa GyrB proteins bearing polyhistidine tags at their respective C-terminal and N-terminal ends were purified to apparent homogeneity by one-step nickel chelate column chromatography and were free of host E. coli topoisomerase activity. Equimolar amounts of the gyrase subunits reconstituted ATP-dependent DNA supercoiling with comparable activity to gyrase of E. coli and Staphylococcus aureus. In parallel, S. pneumoniae topoisomerase IV ParC and ParE subunits were similarly expressed in E. coli, purified to near homogeneity as 93- and 73-kDa proteins, and shown to generate efficient ATP-dependent DNA relaxation and DNA decatenation activities. Using the purified enzymes, we examined the inhibitory effects of three paradigm fluoroquinolones—ciprofloxacin, sparfloxacin, and clinafloxacin—which previous genetic studies with S. pneumoniae suggested act preferentially through topoisomerase IV, through gyrase, and through both enzymes, respectively. Surprisingly, all three quinolones were more active in inhibiting purified topoisomerase IV than gyrase, with clinafloxacin showing the greatest inhibitory potency. Moreover, the tested agents were at least 25-fold more effective in stabilizing a cleavable complex (the relevant cytotoxic lesion) with topoisomerase IV than with gyrase, with clinafloxacin some 10- to 32-fold more potent against either enzyme, in line with its superior activity againstS. pneumoniae. The uniform target preference of the three fluoroquinolones for topoisomerase IV in vitro is in apparent contrast to the genetic data. We interpret these results in terms of a model for bacterial killing by quinolones in which cellular factors can modulate the effects of target affinity to determine the cytotoxic pathway.

scholarly journals Amoxicillin Is Effective against Penicillin-Resistant Streptococcus pneumoniae Strains in a Mouse Pneumonia Model Simulating Human Pharmacokinetics

2006 ◽  
Vol 51 (1) ◽  
pp. 208-214 ◽  
Author(s):  
Pierre Abgueguen ◽  
Esther Azoulay-Dupuis ◽  
Violaine Noel ◽  
Pierre Moine ◽  
Veronique Rieux ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Survival Rates ◽  
Detection Threshold ◽  
Treatment Completion ◽  
Community Acquired Pneumonia ◽  
High Dose ◽  
Human Pharmacokinetics ◽  
Bacterial Clearance ◽  
Bacterial Killing ◽  
Tolerant Strain

ABSTRACT High-dose oral amoxicillin (3 g/day) is the recommended empirical outpatient treatment of community-acquired pneumonia (CAP) in many European guidelines. To investigate the clinical efficacy of this treatment in CAP caused by Streptococcus pneumoniae strains with MICs of amoxicillin ≥2 μg/ml, we used a lethal bacteremic pneumonia model in leukopenic female Swiss mice with induced renal failure to replicate amoxicillin kinetics in humans given 1 g/8 h orally. Amoxicillin (15 mg/kg of body weight/8 h subcutaneously) was given for 3 days. We used four S. pneumoniae strains with differing amoxicillin susceptibility and tolerance profiles. Rapid bacterial killing occurred with an amoxicillin-susceptible nontolerant strain: after 4 h, blood cultures were negative and lung homogenate counts under the 2 log10 CFU/ml detection threshold (6.5 log10 CFU/ml in controls, P < 0.01). With an amoxicillin-intermediate nontolerant strain, significant pulmonary bacterial clearance was observed after 24 h (4.3 versus 7.9 log10 CFU/ml, P < 0.01), and counts were undetectable 12 h after treatment completion. With an amoxicillin-intermediate tolerant strain, 24-h bacterial clearance was similar (5.4 versus 8.3 log10 CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log10 CFU/ml. Similar results were obtained with an amoxicillin-resistant and -tolerant strain. Day 10 survival rates were usually similar across strains. Amoxicillin with pharmacokinetics simulating 1 g/8 h orally in humans is bactericidal in mice with pneumonia due to S. pneumoniae for which MICs were 2 to 4 μg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.

scholarly journals Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

2010 ◽  
Vol 54 (6) ◽  
pp. 2525-2533 ◽  
Author(s):  
Robert Bucki ◽  
Katarzyna Leszczyńska ◽  
Fitzroy J. Byfield ◽  
David E. Fein ◽  
Esther Won ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Glucocorticoid Receptors ◽  
Fluorescent Protein ◽  
Lipoteichoic Acid ◽  
Bacterial Strains ◽  
Bacterial Killing ◽  
Antibiotic Resistant ◽  
Anti Inflammatory ◽  
Green Fluorescent

ABSTRACT The rising number of antibiotic-resistant bacterial strains represents an emerging health problem that has motivated efforts to develop new antibacterial agents. Endogenous cationic antibacterial peptides (CAPs) that are produced in tissues exposed to the external environment are one model for the design of novel antibacterial compounds. Here, we report evidence that disubstituted dexamethasone-spermine (D2S), a cationic corticosteroid derivative initially identified as a by-product of synthesis of dexamethasone-spermine (DS) for the purpose of improving cellular gene delivery, functions as an antibacterial peptide-mimicking molecule. This moiety exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa present in cystic fibrosis (CF) sputa, and Pseudomonas aeruginosa biofilm. Although compromised in the presence of plasma, D2S antibacterial activity resists the proteolytic activity of pepsin and is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage (BAL) fluid. D2S also enhances S. aureus susceptibility to antibiotics, such as amoxicillin (AMC), tetracycline (T), and amikacin (AN). Inhibition of interleukin-6 (IL-6) and IL-8 release from lipopolysaccharide (LPS)- or lipoteichoic acid (LTA)-treated neutrophils in the presence of D2S suggests that this molecule might also prevent systemic inflammation caused by bacterial wall products. D2S-mediated translocation of green fluorescent protein (GFP)-labeled glucocorticoid receptor (GR) in bovine aorta endothelial cells (BAECs) suggests that some of its anti-inflammatory activities involve engagement of glucocorticoid receptors. The combined antibacterial and anti-inflammatory activities of D2S suggest its potential as an alternative to natural CAPs in the prevention and treatment of some bacterial infections.

scholarly journals R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

2012 ◽  
Vol 18 (7) ◽  
pp. 1086-1095 ◽  
Author(s):  
Arie J. Hoogendijk ◽  
Joris J. T. H. Roelofs ◽  
JanWillem Duitman ◽  
Miriam H. P. van Lieshout ◽  
Dana C. Blok ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lung Inflammation ◽  
Lipoteichoic Acid

scholarly journals Unique poly(glycerophosphate) lipoteichoic acid and the glycolipids of a Streptococcus sp. closely related to Streptococcus pneumoniae

2000 ◽  
Vol 267 (17) ◽  
pp. 5520-5530 ◽  
Author(s):  
Peter Roethlisberger ◽  
Naoko Iida-Tanaka ◽  
Klaus Hollemeyer ◽  
Elmar Heinzle ◽  
Ineo Ishizuka ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lipoteichoic Acid

scholarly journals Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection

2016 ◽  
Vol 23 (3) ◽  
pp. 219-227 ◽  
Author(s):  
Ana CG Salina ◽  
Tais P Souza ◽  
Carlos H Serezani ◽  
Alexandra I Medeiros
Keyword(s):  
Streptococcus Pneumoniae ◽  
Prostaglandin E2 ◽  
Mannose Receptor ◽  
Scavenger Receptors ◽  
Apoptotic Cells ◽  
Jurkat T Cells ◽  
Bacterial Killing ◽  
Effector Functions ◽  
Ep Receptor ◽  
Pka Pathway

Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE2 production, activation of the EP2–EP4/cAMP/PKA pathway and inhibition of H2O2 production. Our data suggest that the PGE2 produced by AMs during efferocytosis inhibits H2O2 production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2–EP4/cAMP/PKA pathway.

scholarly journals Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

2002 ◽  
Vol 46 (12) ◽  
pp. 4029-4034 ◽  
Author(s):  
Ayman M. Noreddin ◽  
Danielle Roberts ◽  
Kim Nichol ◽  
Aleksandra Wierzbowski ◽  
Daryl J. Hoban ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Compartment Model ◽  
Free Drug ◽  
Pharmacodynamic Modeling ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Initial Inoculum ◽  
Drug Concentrations

ABSTRACT The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug Cp maximum of 2 μg/ml, t 1/2 of 6 h; in ELF, C ELF(total) maximum of 35μg/ml, t 1/2 of 6 h; CELF(free) maximum of 14 μg/ml, t 1/2 of 6 h). Starting inocula were 106 CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of ≥90% (AUC0-24/MIC ratio, ≥61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC0-24/MIC ratios of ≥30.5 to 38) resulted in a 1.2 to 2.0 log10 CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of ≤8% (AUC0-24/MIC ratio, ≤17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 μg/ml. However, mef(A) isolates for which MICs are ≥16 μg/ml along with erm(B) may result in bacteriological failures.

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